title: Shox2 is a molecular determinant of depot-specific adipocyte function.
abstract: Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat-specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of β3 adrenergic receptor (Adrb3) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.forename: Stephane
authors.initials: S
authors.lastname: Gesta
authors.forename: John
authors.initials: J
authors.lastname: Cobb
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D004032:Diet; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance; D008066:Lipolysis; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C484663:Shox2 protein, mouse
keywords: adipose depots; developmental genes; lipid metabolism